Abstract and Introduction
Background: Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here.
Methods: Adults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments.
Results: Fourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: − 33.6 and − 0.7, respectively), Patient and Physician Global Assessments (CFB: − 4.6 and − 5.7, respectively), and joint involvement (CFB: − 5.6, − 8.4, − 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR ("cough") occurred and no new safety signals were identified.
Conclusion: Pegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes.
Trial registration: ClinicalTrials.gov (NCT03635957)
Hyperuricemia and gout affect 32.5 million and 9.2 million people, respectively, in the USA. Chronic hyperuricemia results in monosodium urate crystal deposition throughout the body, including in the kidneys, heart, larynx, and bowel, and is associated with a specific set of comorbidities, including cardiovascular disease,[3–7] hypertension,[7,8] diabetes,[7,9] and chronic kidney disease.[7,10] Even in patients with asymptomatic hyperuricemia, inflammation levels are elevated.[11,12] When oral urate-lowering therapies (ULTs), including both xanthine oxidase inhibitors and uricosurics,[13,14] are not tolerated, contraindicated, or no longer effective, refractory or uncontrolled gout can occur. The clinical hallmarks of uncontrolled gout include recurrent debilitating flares, chronic synovitis, chronic gout-related pain, tophi, urate-related joint damage (as visible on radiography), and urate deposition (as visible on dual-energy computed tomography [DECT] or ultrasound imaging). Uncontrolled gout further increases the risk for cardiovascular disease, diabetes, and chronic kidney disease as well as the burden on quality of life resulting from ongoing pain and high levels of disability.[16,17] Unfortunately, patients with chronic refractory gout are left with limited treatment options for urate lowering.
Pegloticase is an effective medication for treating uncontrolled gout, but some patients develop anti-drug antibodies (ADAs), which are associated with loss of urate-lowering efficacy[18–20] and increased infusion reactions (IRs).[18,19] In the phase 3 clinical trials, the pooled pegloticase responder rate at the approved dose regimen was 43.5% during month 6 (42% during months 3 and 6 combined), with most high-titer ADA patients having loss of pegloticase efficacy within 6 months. The 6-month results from the MIRROR open-label trial suggest that methotrexate (MTX) administered in conjunction with pegloticase nearly doubles the responder rate (79% during month 6 [11 of 14 patients], 95% confidence interval: 49–95%) with lower IR occurrence and otherwise similar safety profile as pegloticase monotherapy. Furthermore, 12-month MIRROR open-label safety and efficacy findings indicate that urate-lowering is sustained over the long-term in patients remaining on therapy with both pegloticase and methotrexate. Here, longer-term (12-month) exploratory endpoints of the MIRROR open-label trial are reported, including joint involvement, Health Assessment Questionnaire, and Global Assessments of Gout.
Arthritis Res Ther. 2022;24(281) © 2022 BioMed Central, Ltd.
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